Nasogastric enteral formulations

ABSTRACT

The present invention relates to a nasogastric formulation comprising an amino acid source, a carbohydrate source, a lipid source, and a fatty acid delivery agent wherein the fatty acid has a bond hydrolysable in the colon to deliver free fatty acids such as short chain fatty acid acetate without having an adverse affect on the capacity to pass through a tube for tube feeding.

This application is the National Phase of International ApplicationPCT/AU00/00792 filed on Jun. 30, 2000 which designated the U.S. and waspublished under PCT article 21(2) in English.

This invention relates to an enteral formulation suitable fornasogastric administration.

BACKGROUND OF THE INVENTION

Humans and animals with certain conditions are either not able to orpreferably do not take nutrition by conventional means. Such individualscan have sustenance administered parenterally such as by the use of avenous drip or enterally in the form of a specific liquid formulationdelivered via intubation of the gastrointestinal tract. There areobvious disadvantages to administering sustenance parenterally in so faras the risk of trauma and infection is greatly increased and the rate atwhich material that can be administered is quite low. Moreover, certaintypes of material cannot be administered, for example, dietary fibre.Additionally there are risks in having a gastrointestinal system whichis inactive for any extended length of time due to the absence of fibreand other poorly digestible materials as it can lead to atrophy and to arange of other histo-pathological changes to various regions and even inthe shorter term diminishes the well being of an individual.

Food formulations for clinical conditions may be administered orally andthat is the preferred route as it is the normal means of food ingestion.However, for certain specific conditions it is necessary or at leastadvantageous to administer the formulation enterally by a tube feedingsystems such as by a nasogastric tube which delivers nutrients directlyto the stomach.

The requirement for enteral feeding might be relatively short term forexample where a patient or other individual is treated for a clinicalcondition where the patient may be unable to masticate, swallow orretain conventional forms of food. Alternatively the patient might besuffering from a condition that requires longer term treatment andenteral feeding might be administered at the residence of the patientfor a prolonged period.

Enteral formulations, especially those, used for short periods areintended to replace the normal diet and so contain materials thatreflect such diets, and these include nitrogenous material such asproteins, protein hydrolysates, peptides or amino acids, carbohydrates(whole or partially hydrolysed), lipids, vitamins and essential mineralsare thus generally delivered as emulsions. No particular attention isgiven to maintaining an active colon for short term administration. Itis recognised that an inactive large bowel in the longer term isundesirable, and commercial formulations which have “added fibre” areavailable, with a view of maintaining such activity. These formulationsgenerally include a fermentable resistant starch or a fermentablenon-starch carbohydrate that is resistant to digestion by human enzymesin the small bowel but is fermentable by the microflora in the largebowel. Cope et al. in U.S. Pat. No. 5,403,826 refer to the inclusion ofdietary fibre to enteral formulations and exemplify the use of soypolysaccharides. These polysaccharides are in large part digested in theileocaecal region and the proximal large bowel with none or only smallamounts reaching the distal bowel (Annison. G. & Topping, D. L. (1994)Resistant starch: Chemical structure vs physiological function. Ann.Rev. Nutr. 14: 297–320) and the levels used in the formulation are quitelow. Garleb et al. in U.S. Pat. No. 5,444,054 refers to the inclusion ofdietary fibres and indigestible oligosaccharides so that SCFAs may beformed in the large bowel. Reference is also made to Green et al in U.S.Pat. No. 5,792,754 where a mixture of resistant fibre is provided whichis claimed to provide for deliver a balance of activity alone the lengthof the gastrointestinal tract. The inventors believe that Cope, Garleband Green, as well as commercially available formulations all sufferfrom the inability to deliver sufficient fibre to give an adequateelevation of short chain fatty acid (SCFA) levels in the colon.

Whilst the “fibre added” enteral formulations do go some way toalleviating the problems of a totally inactive gastrointestinal tractthe degree of fermentation in the large bowel is simply not enough,particularly for patients that are fed enterally for extended periods.The relatively low level of delivery of fermentable fibre to the colonwould be exacerbated where the medical treatment received by the patienthas a marked impact on the microflora of the patient which thereforecannot or is inefficient at transforming fibre to SCFAs.

A consequence of long term enteral feeding is the manifestation ofcertain disorders of the caecum and colon due to at least in partinactivity and lack of nutrient. Such disorders might include atrophyand perforation of the bowel, the overgrowth of the normal microflora ofthe bowel by organisms which might potentially be pathogens anddiarrhoea.

One primary restriction on the capacity to deliver is the quantity offibre that can physically be delivered through a feeding tube such as anasogastric tube rather than a reluctance to increase levels in entericformulations. Nasogastric tubes are rather difficult to put into placeand are unpleasant for the patient and thus the outside diameter of thetube is kept as small as possible with a consequent small internaldiameter. Not only is the internal diameter a consideration but a pumpor gravity is generally used to move the formulation through the tube.This means that the liquid within the tube is also under compression, sothat any viscosity of the fluid is further compounded. The intrinsicviscosity of soluble fibre and protein in the partially or fullyhydrolysed state can be high and thus poses a limitation. Some of thecomponents of these formulation may be delivered as insolublesuspensions, however, the provision of insoluble suspensions isparticularly undesirable for nasogastric application, because of thedifficulties associated with sedimentation and phase separation and thedifficulty of resorting to increased viscosities to alleviate settlingout. The very much preferred approach to nasogastric application is toprovide the solids in soluble form, which are supplied together with thefat component to form an emulsion.

A suggestion has been made in U.S. Pat. No. 5,919,822 by Cotter et al.in light of the restricted capacity of enteral formulation to includefibre provide SCFAs in enteral and parenteral formulations. Cotter et aldo however not provide any data in terms of the efficacy of the deliveryof SCFA, and it is believed that the predominance of the SCFA will bedegraded before reaching the large bowel so that the formulationprovides little benefit especially to the distal colon. The directdelivery of SCFA has only be achieved by an enema (Sheppach et al.(1992) Gastroenterology: 10: 51–56), or when complexed with a carrier(WO 95/13801).

It is believed by the inventors that the enteral formulations suggestedto date do not supply an adequate amount of short chain fatty acids tothe large bowel or at least do so inefficiently. Additionally in theevent of a highly altered microflora of the large bowel which mightresult from chemotherapy or antibiotic treatment, the often quitecomplex transformation that are required to produce beneficial shortchain fatty acids cannot be performed efficiently. Furthermore providingan enteral formulation that delivers benefit, in the form of elevatedamounts of short chain fatty acids to the large bowel in a short timespan has to the knowledge of the inventors not been done before.

For the purposes of this specification the word “comprising” means“including but not limited to”, and the word “comprises” has acorresponding meaning. Also a reference within this specification to adocument is not to be taken as an admission that the disclosure thereinconstitutes common general knowledge in Australia.

OBJECT OF THE INVENTION

It is an object of the present invention to provide an enteralformulation for nasogastric application which alleviates or reduces thedisadvantages of the aforementioned problems, or at least provides thepublic with an choice.

SUMMARY OF THE INVENTION

WO 95/13801 in the name of the Commonwealth Scientific and IndustrialResearch Organisation discloses a means of enhancing the levels of shortchain fatty acids delivered to the bowel to alleviate or overcome somedisorders of the large bowel, however there is no indication that thismaterial can be used in enteral tube feeding.

The present inventors now recognise that there are prospects ofdeveloping a workable enteral formulation suitable for nasogastricapplication which can reduce the problems associated with aphysiologically inactive large bowel that are associated with enteraltube feeding.

It has been found that the fatty acid delivery agent can be deliveredvia an enteral tube to provide an elevated level of fatty acid in thecolon. Additionally it has been found that the elevated level can beachieved remarkably quickly and without prior adaptation, and that atleast one form of the fatty acid delivery agent has a stabilising effecton nasogastric formulations.

This invention provides for an enteral formulation suitable for use innasogastric feeding, which includes a fatty acid delivery agent forenhanced delivery of fatty acids to the large bowel that have abeneficial effect in the large bowel. The fatty acids in the fatty aciddelivery agent are covalently bonded to a carrier by a bond that isselectively cleavable in the large bowel to give free fatty acids. Thefatty acid delivery agent is either soluble in water or the lipid phaseof the prepared formulation or alternatively can be rendered stable byan emulsifying agent such as by packaging into liposomes. Mostpreferably the fatty acid delivery agent is soluble in water.

The fatty acids are selected as being of benefit to the health of theindividual human or animal. The fatty acid might be one or more of theshort chain fatty acids, which in the present context might be taken ashaving a carbon chain length of between 1 and 10. Preferably however thechain length is between 2 and 4, encompassing acetate, propionate andbutyrate, from the literature these three SCFAs have the most evidenthealth benefits. Alternatively a broader range of fatty acids arecontemplated by this invention, which fatty acids play a role inbenefits other than bowel health directly, and such fatty acids might beselected from the omega 3 fats (such as eicosapentaenoic acid.

EPA and docosahexenoic acid DHA, linolenic acid), omega 6 fats (such aslinoleic acid), stearadonic acid, and conjugated fatty acids (such asconjugated linoleic acid). These fats may be given as triacylglycerolsor partial glycerides or as phospholipids bonded to the carrier.

The carrier can be varied greatly and might include natural dietaryfibre or non-digestible oligosaccharides or other biological molecules,alternatively a synthetic polymer might be used as the carrier. Thecarrier might thus be contemplated as being a faecal bulking agent. Theinvention however contemplates that the carrier will be capable of beingused as an energy source for normal large bowel microflora. Generally itis anticipated that the carrier will preferably be a carbohydrate sothat on cleavage of the fatty acid from the carrier, the carrier canthen be used, firstly as a means for increasing the microflora of thelarge bowel, and secondly can be metabolised by at least a proportion ofthe microflora to form SCFA, to further enhance health benefits to thelarge bowel. More preferably the carrier is a starch and most preferablya resistant starch.

The degree of substitution is also of relevance in so far as manycarriers that might be contemplated such as for example hydrolysedcarbohydrates would have a tendency to exert osmotic effects that might,for example, give rise to diarrhoea. The latter condition is predisposedto some extent already by the adoption of a radically different diet andthe absence of SCFA which facilitates fluid absorption. Whereas withsuitable substitution the nature of a carrier molecule can be modified,so as to be a little more conducive to water retention by the largebowel. Additionally where the carrier is a natural carbohydrate such asa starch the substitution has a tendency to minimise gelatinisation,especially under heat treatment, thereby maintaining the resistance todigestion of the formulation by human enzymes in the small intestineafter treatment for sterilisation. Additionally this will impactpositively on the physical characteristics of the prepared formulation.

Examples of the bond between the fatty acid and the carrier are amide orester bonds.

Other examples of fatty acid delivery agents can be determined byreference to WO 95/13801 which document is hereby incorporated byreference.

In one aspect the invention could be said to reside in an enteralformulation for nasogastric delivery including,

-   -   a) an amino acid source    -   b) a carbohydrate source,    -   c) a lipid source, and    -   d) a fatty acid delivery agent, being a fatty acid covalently        bonded to a carrier molecule by a bond hydrolysable in the colon        to thereby release the fatty acid.

In a preferred form the viscosity of the formulation in no greater than40 centipoise (cP) when measured at 25° C. (using a Brookfield Dv-3programmable rheometer with a cp40 cone) for ease of delivery, and morepreferably the viscosity is no more than about 20 cP when measured at25° C.

It is also preferred that the formulation is capable of being stored forat least 24 hours without forming a gel or precipitated or other nonhomogenous system that is not readily resuspended. Further formation ofclumping or settling out is not preferred, because of the risk of notdelivering the full formulation. The fibre component or fatty aciddelivery agent is the component that will form the clumping or the geland thus may result in the incomplete delivery of the formulation.

In a further aspect of the present invention the nasogastric elementaldiet formulation include

-   a) an amino acid source-   b) a sugar source-   c) a lipid source-   d) a mineral source-   e) a vitamin source-   f) and a fatty acid delivery agent as discussed and described    herein.

The sources of a) to e) are generally conventional sources selected fromthose that do not interfere with nasogastric application, and do notadversely react with f) or react positively therewith. The sugar sourcemay take the form of carbohydrates, which in part form the carrier ofthe fatty acid delivery agent where the carrier is a carbohydrate.Preferably however these are added separately so that metabolism andabsorption can be achieved in the small bowel. The level of f) issufficient to deliver a beneficial quantity of the combination of abulking agent and fatty acid to the large bowel, and preferably thelevel of f) is in the range of greater than 5 grams per day, with themaximum being limited by viscosity constraints, however levels of up to80 grams per day should be achievable by at least some embodiments,however more preferred is about 40 grams per day.

It is anticipated that the fatty acid delivery agent is made by taking acarrier and substituting fatty acids onto the carrier.

The daily dosage rate for a fatty acid delivery agent which takes theform of a resistant maize starch substituted by 2–4 carbon length SCFAat a degree of substitution of 0.25 could be in the range of 5 to 80grams per day. This might be compared to a similar level of resistantstarch requiring to be delivered at a rate in excess of 25 grams perday, to give the amount of SCFA required and demonstrated in WO95/13801,and by Sheppach et al. (1992) Gastroenterology; 10: 51–56). Given thatthe level of fluid delivery of enteral feeds is generally in thevicinity of 1 liter or up to 2 liters, the level of conventionalcarbohydrate required to be present (about 2.5% w/v), in addition toother constituents (such as those known to the skilled addressee) of theenteral feed is in excess of what would, by reason of viscosity, bereadily deliverable through a nasogastric tube by a resistant starch.Beneficial effects of the fatty acid delivery agent may however be ofvalue at a greater range of levels, and perhaps as low as 0.5% w/v ofthe final enteric formulation, the upper limit might be determined bysolubility and thus might perhaps account for as much as 5% of the finalenteric formulation as administered through the nasogastric tube.

Additionally the benefit of the present formulation is that the level ofa predetermined fatty acid can be increased in the large bowel. Thus,for example, a butyrilated starch could be added to specificallyincrease the level of butyrate in the large bowel.

In the context of this specification the enteral composition is referredto as suitable for administration via a nasogastric tube, however theadministration need not be limited thereto, but might also beadministered via gastronomy and jejunostomy tubes, or may be orallyconsumed as a beverage.

A further aspect of the invention might be said to reside in a method ofdelivering a fatty delivery agent in a physiologically acceptable mediumthrough a feeding tube to elevate the level of SCFA, the fatty aciddelivery agent being a fatty acid covalently bonded to a carriermolecule by a bond hydrolysable in the colon to thereby release thefatty acid. This need not have all the normal nutritional requirementsof an individual, but might be delivered quite independently of tube fedor other enteral formulations. This could be given as a separate feed,particularly where there is a wish to quickly boost the level of therelevant fatty acid in the large bowel, and it is anticipated that aformulation having quite high levels of fatty acid delivery agent couldbe delivered, perhaps as high as 30% or at least 25%. Certainly 20% ofthe exemplified fatty acid delivery agent could be made and it isanticipated that a higher level could be delivered. It will beunderstood however that generally it would be convenient to deliver thefatty acid delivery agent together with the other nutritionalrequirements of the individual concerned.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Is a plot of the results of example 3 wherein the butyrateconcentration of the caecum of a rat was determined at time points 2, 4and 6 hours after ingestion of starch acetate ▪ or a control fed starch3401C ♦,

FIG. 2 Is a plot of the results of examples 3 and 4 wherein the pool ofacetate of the caecum of a rat was determined at time points 2, 4 and 6hours after ingestion of starch acetate ▪ or a control fed starch 3401C♦,

FIG. 3 Is a plot of the results of examples 3 and 4 wherein the pool ofpropionate of the caecum of a rat was determined at time points 2, 4 and6 hours after ingestion of starch acetate ▪ or a control fed starch3401C ♦,

FIG. 4 Is a plot of the results of examples 3 and 4 wherein the pool ofbutyrate of the caecum of a rat was determined at time points 2, 4 and 6hours after ingestion of starch acetate ▪ or a control fed starch 3401C♦, and

FIG. 5 Is a plot of the results of examples 3 and 4 wherein the pool oftotal short chain fatty acids of the caecum of a rat was determined attime points 2, 4 and 6 hours after ingestion of starch acetate ▪ or acontrol fed starch 3401C ♦.

DETAILED DESCRIPTION OF THE EXEMPLIFIED EMBODIMENTS EXAMPLES

Methods—Evaluation of Acetylated Starch in Nasogastric Feed Solutions inRats—Effects on Large Bowel Fermentation

A measured dose of the enteral feeding solution including acetylatedstarch was administered by gavage to rats to mimic the ingestion of foodwhilst avoiding the mouth. Then, at intervals of approximately twohours, caecal digesta was collected and SCFA levels determinedsubsequently. Other changes in the intracolonic environment, relevant tobowel health, were also monitored.

For each study, adult rats (Sprague Dawley, 250–350 g) were maintainedon a standard basal colony diet (Joint Stock Ration available fromRidley Agri Products, Murray Bridge. South Australia) before beingallocated to two or three treatments and three time-point slaughtergroups. After depriving rats of food overnight, they were gavage-fed (4ml) a slurry containing 1 g of either 3401C maize starch (Control, ahigh amylose starch available from Goodman Fielder, Melbourne,Australia) or acetylated starch (made according to Example 6). Gavagefed through an FG8 tube presterilised (available from Indoplas Pty LtdSydney). The FG8 tube was 40 cm in length with a 1 mm internal diameterand a 2 mm external diameter and positioned through the mouth andoesophagus to rest in the stomach. The solutions were forced through theFG8 tube using a syringe. At 2, 4 and 6 hours post-gavaging, rats wereasphyxiated by CO₂ the abdominal cavity opened and the caecum excised.Caecal contents were expressed, weighed, diluted with a known quantityof internal SCFA standard (heptanoic (caproic) acid) and homogenised.After centrifugation (3000 rpm) supernatant pH was measured and then analiquot stored frozen to await analysis of SCFA. SCFA analysis wasperformed by the method described in Topping et al. (1993) J Nutr. 123:133–143.

Example 1 Physical Properties of Various Starch Suspensions

All feeding solutions prepared by suspending 1 g of designated starch in4 ml of water. This was not sterilised.

-   -   Acetylated Starch—thin slurry    -   3401C Control starch—thin slurry

Example 2 Pilot Study of Gavage Feeding with Digestible Starch andAcetylated Starch

This study was a pilot study using 2 female rats of about 400 g. Thecontrol starch 3401C was compared with acetylated starch produced byexample 6. After overnight food deprivation rats were dosed and killedtwo hours later. The stomach of each of the rats were empty of contents,product was visible in small intestine.

Results

TABLE 1 Starch Caecal contents (g) Ph 3401C 1.90 7.82 Acetylated starch1.90 7.58

TABLE 2 Starch Acetate Propionate Butyrate 3401C 22.9 8.8 3.9 Acetylatedstarch 25.7 8.9 6.6

The measurement of the short chain fatty acids is a calculation of thetotal caecal content.

There is a numerically greater amount of butyrate present in the caecumof the rat fed Acetylated starch when compared to the rat fed 3401Ccontrol starch. There is no appreciable change in the amount of caecalcontent, pH of the caecum, or the levels of acetate or propionate.

Example 3 Time Trial of Gavage Feeding

This trial involved 6 male rats weighing about 330 g. The starches usedwere 3401C control starch or acetylated starch made in accordance withthe method set out in example 6. Feed preparation of 1.25 g of starchwere added to 5 ml water and used fresh. Each dosage was 4 ml.

Rats dosed with various starches and killed 2, 4 and 6 hours later. Thestomachs of each of the rats was empty of contents but products visiblein small intestine. The contents of the caeca were processed as set outin the description of the methods.

Results

TABLE 3 Starch Caecal contents (g) Ph 3401C - 2 h 2.22 7.62 3401C - 4 h1.65 7.72 3401C - 6 h 2.55 7.27 Acetylated starch - 2 h 1.60 7.72Acetylated starch - 4 h 1.80 6.97 Acetylated starch - 6 h 2.24 6.14

TABLE 4 Starch Acetate Propionate Butyrate 3401C - 2 h 21.1 6.7 4.73401C - 4 h 22.0 7.6 4.1 3401C - 6 h 31.4 10.9 6.5 Acetylated starch -24.6 7.7 4.5 2 h Acetylated starch - 30.5 8.0 6.4 4 h Acetylatedstarch - 34.5 10.1 11.4 6 h

It can be seen that there is a numerical difference in the level ofbutryate found in the caeca of rats both after 4 hours and 6 hours aftergavage feeding. FIG. 1 is a plot of the caecal butyrate concentration.

Example 4 Time Course Effect of Acetylated Starch

This trial involved 15 male rats weighing about 370 g. The starches usedwere 3401C control starch or acetylated starch made in accordance withthe method set out in example 6. Feed preparation of 1.25 g of starchwere added to 5 ml water and used fresh. Each dosage was 4 ml. a controlwith only water (n=1) was also included.

Rats dosed with various starches and killed 4, 6 and 8 hours later. Thestomach of each of the rats was empty of contents but product wasvisible in small intestine. The contents of the caeca were processed asset out in the description of the methods.

Results

TABLE 5 Propio- Buty- Caecal Starch Time Acetate nate rate Total ContentpH Water Control 4 hr 9.1 4.1 0.8 14.0 2.58 7.52 6 hr 22.9 8.1 1.1 32.12.38 7.44 8 hr 21.1 7.3 0.9 29.3 1.25 7.48 3401C Starch 4 hr 8.5 4.8 0.814.1 1.6 7.63 4 hr 16.2 4.4 2.9 23.5 1.5 7.83 6 hr 6.4 3 0.5 9.9 1.427.64 6 hr 13.9 6.9 1.1 21.9 1.91 7.40 8 hr 31.5 12.2 1.2 44.9 2.64 7.228 hr 22.0 8.2 1.0 31.2 1.54 7.44 Acetylated Starch 4 hr 51.6 11.0 13.976.5 3.47 6.46 4 hr 23.6 6.9 9.7 40.2 2.53 6.43 6 hr 40.8 13.6 14.8 69.22.76 6.36 6 hr 17.5 12.2 15.8 45.5 4.85 6.40 8 hr 30.3 9.4 12.3 52.02.36 6.35 8 hr 43.6 16.1 13.3 73.0 2.94 6.45

Caecal ammonia was also measured in rats killed at 6 hours and there isa significant difference with the control starch 3401C. Control measured10.1 mM as opposed to the acetylated starch measured 4.1 mM. FIGS. 2, 3,4, and 5 are composite figures using data from example 3 and 4, showingthe calculated amount of caecal acetate, caecal propionate, caecalbutyrate and total SCFA (combination of acetate, propionate andbutyrate) times 4 and 6 hours are combined and time 8 is omitted. Thesedata show that in all cases there is an increase in the amount of theSCFA concerned. Using time pooled data it can be seen that all valuesare significant (see table 6 below).

Of interest is to note the lack of appreciable difference between thewater controls and the starch control. There is considerable variationin the numerical values of each sample.

The data in the table below represents the pooled data from the 3401Ccontrol and the rats fed acetylated starch.

TABLE 6 Concentration of individual and total SCFA in the caecum of rategavaged with Acetylated starch A (Example 4) mmol/L 18 18 PropionateButyrate Total Control 16.4 6.6 1.3 24.3 Starch Acetate 34.6 11.5 13.359.4 P value 0.039 0.023 0.001 0.069 Values are least square means of 6male rats per group. Caecal contents were collected at 4, 6, and 8 hourpost gavaging. As there were no significant (P > 0.05) time effectsvalues were averaged across the three sampling time points.

Example 5 Time Course Effect of Acetylated Starch

This trial involved 36 male rats weighing about 330 g. The starches usedwere 3401C control starch or acetylated starch made in accordance withthe method set out in Example 6. Feed preparation of 1.25 g of starchwere added to 5 ml water and used fresh. Each dosage was 4 ml, a controlwith only water (n=1) was also included.

Rats dosed with various starches and killed 2.4 and 6 hours later. Thestomachs of each of the rats was empty of contents but products visiblein small intestine. The contents of the caeca were processed as inexample 2.

TABLE 7 Caecal Caecal Control Content Time Starch Content Starch (g) pH(hours) acetate (g) pH  1 1.42 7.10 2  1 1.91 7.51  2 1.27 7.29  2 3.017.25  3 0.83 7.50  3 0.56 7.20  4 0.42 6.97  4 2.26 7.12  5 0.40 7.53  51.89 7.25  6 1.12 7.23  6 1.51 6.85 Mean 0.91 7.27 Mean 1.86 7.20 SD0.43 0.22 SD 0.81 0.21  7 2.36 7.30 4  7 0.45 6.27  8 1.12 7.08  8 1.226.82  9 1.70 7.27  9 1.48 6.63 10 2.78 7.07 10 1.34 6.94 11 2.95 6.74 112.99 6.60 12 0.14 7.26 12 1.85 6.12 Mean 1.84 7.12 Mean 1.56 6.56 SD1.08 0.21 SD 0.84 0.32 13 1.13 6.89 6 13 2.64 5.93 14 0.32 7.03 14 1.705.91 15 1.73 7.18 15 0.52 5.78 16 0.66 7.06 16 2.54 6.00 17 1.13 7.30 172.72 6.01 18 2.33 6.63 18 3.16 6.36 Mean 1.22 7.02 Mean 2.21 6.00 SD0.73 0.23 SD 0.96 0.20

TABLE 8 Caecal SCFA pool (mM) Control Propio- Buty- Time Starch Propio-Buty- Starch Acetate nate rate Total (h) Acetate Acetate nate rate Total 1 48.5 13.1 5.6 67.1 2  1 22.8 11.6 6.9 41.3  2 24.0 11.1 4.8 39.8  219.5 14.0 6.5 40.0  3 4.2 3.1 1.9 9.1  3 15.7 4.7 3.0 23.4  4 12.6 3.72.0 18.3  4 70.3 23.1 12.8 106.3  5 10.9 3.6 1.5 16.0  5 43.4 15.0 8.566.8  6 16.0 6.5 2.1 24.6  6 46.5 15.9 9.1 71.5 Mean 19.4 6.8 3.0 29.2Mean 36.4 14.1 7.8 58.2  7 68.2 23.0 12.5 103.7 4  7 5.8 1.5 1.3 8.7  833.0 9.5 4.7 47.1  8 24.2 5.0 5.3 34.5  9 13.6 6.7 2.9 23.1  9 45.1 8.57.9 61.6 10 75.2 29.4 14.7 119.2 10 25.6 8.1 4.1 37.8 11 63.2 18.2 23.6105.0 11 66.5 19.1 20.3 106.0 12 2.9 1.0 0.7 4.6 12 53.6 13.5 13.0 80.1Mean 42.7 14.6 9.9 67.1 Mean 36.8 9.3 8.7 54.8 13 31.6 8.6 5.5 45.7 6 1359.1 16.3 16.9 92.3 14 10.0 2.5 2.5 15.0 14 35.9 12.4 8.6 56.8 15 38.913.0 7.3 59.2 15 16.8 3.7 2.7 23.2 16 20.2 5.9 3.2 29.3 16 33.5 8.1 7.148.8 17 30.5 8.0 4.4 42.8 17 109.5 31.6 19.1 160.2 18 51.8 15.3 11.678.7 18 119.1 30.8 30.3 180.2 Mean 30.5 8.9 5.8 45.1 Mean 62.3 17.2 14.193.6

There are no statistically significant time effects. Examination of datashow that SCFA was highest at 6 hours in rats fed acetylated starch, butexamination of table 7 shows a continuous decline in pH. This suggeststhat SCFA generation and attendant change of pH was occurring before asignificant difference in actual amount of SCFA was measured. The 4 hourvalues are out of line with that observation and those of the earlierdata and for that reason the 2 hour and 6 hour time points only wereanalysed.

TABLE 9 Caecal pools of individual and total SCFA in rats gavaged withacetylated starch in Example 5, 2 and 6 hour time point only mmol/LDietary Group Acetate Propionate Butyrate Total Control 24.9 7.9 4.437.1 Starch Acetate 49.3 15.6 11.0 75.9 P value 0.033 0.017 0.009 0.022Values are least squares means of 12 male rats per group. Caecalcontents collected at 2 and 6 hours post gavaging. Data for 4 hourcollection excluded. As there were no significant (P > 0.05) timeeffects vales were averaged across the two sampling time points.

It can thus be seen that there is a statistically significant increasein the amount of the individual SCFA present in the caeca of the ratsfed with acetylated starch when compared with the caeca of rats fedcontrol starch.

Discussion

It can be seen that significant levels of acetylated starch can beintroduced into the bowel of the experimental animals and further thatthese result in significant increases in the amounts of SCFA in thecaeca of these animals. These SCFA are known to have a significanteffect on bowel health, and in particular butyrate is implicated inregeneration and repair of colonocytes.

An important aspect of these results is the extremely short time spanover which the physiological increase in the amount of SCFA is elicitedwithout prior adaptation of the animals. The changes occur in less thantwo hours, the lower time limit is not known. The significance of thatis that there is then provided a means of very rapid delivery of SCFA tothe bowel using an enteral feeding method. It is speculated that thereis no need for the resident microflora to significantly adapt to the newsource of SCFA. This has implications for individuals who could benefitfrom such a rapid and effective delivery mode of SCFA. Given theubiquity of the esterases it is likely that the presence of any bacteriain the large bowel will be able to cleave the SCFA from the carrier, andtherefore individuals with microflora that might be compromised byreason of treatments such as antibiotics or chemotherapy will also bereadily able to enable delivery of the SCFA.

This has particular significance to treatment where such delivery isdesirable. In instances where a patient undergoes surgery, for example acolonic resection, and requires optimal conditions for repair of thebowel, a nasogastric formulation for delivery of SCFA to the large bowelis highly desirable. Thus the formulation may be useful not only for thelong term health where a patient might suffer as a result of a lack ofactivity in the large bowel, but also for the short term such as inenteral feed formulations used for example in intensive care units ofhospitals.

Example 6 Preparation of Acetylated High Amylose Maize Starch

The following chemicals and materials were used to prepare theacetylated HA (High Amylose) maize starch:

TABLE 10 Reagents HA maize starch [Hi-maize ™] 350 kg. (Goodman FielderAustralia). Water. 560 L. Acetic anhydride. 24.5 L. Hydrogen peroxide[100 vol.] 1.47 L. Sodium hydroxide [0.65M]. As required. Hydrochloricacid [10M]. As required.

The method employed to acetylate the HA maize starch utilized thefollowing protocol;

-   1. Measurement of the required quantity of water into the reaction    vessel.-   2. Addition of the starch.-   3. Adjustment of the pH of the slurry to pH 8.01±0.1 using sodium    hydroxide solution.-   4. Addition of the hydrogen peroxide.-   5. Agitation of the slurry for 45 mins.-   6. Addition of acetic anhydride while simultaneously adding sodium    hydroxide solution.

The pH was maintained in the range 8.0 to 8.5. The reaction wascompleted in less than 30 mins.

-   7. Permit the slurry to mix for 30 mins. The pH was maintained in    the range 8.0 to 8.5.-   8. The pH was adjusted to 5.0 to 6.5 with hydrochloric acid.-   9. The starch was washed, dried and ground [to pass through a 212    Micron screen].-   10. The recovered starch had a degree of substitution of 0.25

Example 7 Nasogastric Feeding Mixtures—Physical Properties

Three mixtures were prepared using acetylated starch at 1%, 2.5% and 5%(g/mL) to a final preparation constituted as set out below

TABLE 11 Ingredients Ingredient g per L Casein 46 Oil* 41 Starch^(#) —Sucrose 33 Vitamin mix 0.4 Mineral mix 4.6 Water 821 ^(#)AcetylatedStarch - 1, 2.5 and 5% *Lecithin was added as 3% of the oil content

The acetylated starch was suspended in 100 to 150 mL of RO (ReverseOsmosis) water and then treated at 100° C. for 50 minutes to gelatinise.

The 11.5 g of casein required for a 250 mL mixture was taken up in anindividual amount of 50 mL of RO water that had 30 drops of 10 mM sodiumhydroxide added to lower the pH. The resulting casein gel was added tothe warm gelatinised starch solution, followed by the oil, lecithin,mineral/vitamin mix and dissolved sucrose. The volume was adjusted to250 mL and mixed by shaking.

Viscosities were measured using a Brookfield DV-3 programmable rheometerwith a cp40 cone.

Flow characteristics were measured by allowing the mixtures to flowunder gravity from a Flexitainer (500 mL Enteral Nutrition Container)through an enteral feeding set (1.5 m long, 3.5 mm bore) connected to aFlexiflow feeding tube (#10F 114 cm long with an end outlet of 2 mminternal diameter plus two side outlet holes of similar diameter). Theflexitainer was 2.6 m high and the feeding tube outlet was 0.9 m abovethe floor to mimic feeding a patient in the sitting position.

TABLE 12 Viscosity measurement of formulations including acetylatedstarch Viscosity Time Mixture cP at 25° C. (Min) 1.0% 7.2  7 min 40seconds 2.5% 13.2 12 min 30 seconds 5.0% 60.8 † Nutrison ™ 19.3 20 min25 seconds †Would not flow through the first tube (3.5 m) *Nutrisonenergy: from Nutricia, Zoetermeer, Holland.

It is anticipated that a solution with a viscosity of about 40cP and ata rate of shear of 120 sec⁻¹ at 25° C. as determined above will be ableto be used through a feeding tube. It is estimated that the limit of theacetylated starch preparation that one could workably deliver using theformulation currently devised is about 4%, however it is anticipatedthat using different formulations that the level might be raised to 5%.

A further test was conducted in relation to 1% solutions of Hi Maize™and the acetylated starch preparation made in accordance with Example 6added to the formulation set out in table 11. These were readilysolubilised and boiled. On storing overnight at 4° C. the HiMaize™preparation formed a hard gel on the bottom of the storage vessel, andcould not readily be dispersed by agitation. It is thought that thishard gel may be formed by the starch which is of a particulate nature,being converted to a retrograde state. Many nasogastric formulationshave a high cation content and appear to have exacerbated gel formationof this nasogastric preparation, whereas in the case of the substitutedversion of the starch no such settling out was seen. In fact theacetylated starch had the properties of a stabiliser of the emulsionformed by the nasogastric formulation because it kept the phases fromseparating, and any particulates from settling.

The capacity to deliver a solution of 4% acetylated starch as a tubedelivered enteral formulation give quite a high capacity to delivernutrients. An usual maximum delivery might be in the order of twoliters, which provides for a maximum delivery of 80 Grams of acetylatedstarch by this route, or indeed with a formulation having 5% thatcapacity will be raised to 100 grams per day. The stated requirement offibre intake per day for a person is 30 grams (Baghurst et al Supplementto Food Australia 48(3) s3–s35, 1996). Of this fibre nearly all willreach the large bowel. If resistant starch was substituted for fibrehere might be a loss during transit through the small intestine and itis estimated that to meet the recommended delivery one might need toprovide 40 grams per day. It is noted however that the fatty aciddelivery agent of the present nasogastric formulation need notnecessarily provide 30 grams. Firstly it might not necessarily be theonly component that provides the benefits of fibre, such as luminalhydration and faecal bulking, and secondly the capacity to deliver thehealth giving SCFA is enhanced because they are readily cleavable formthe carrier. It might thus be feasible that a benefit be effected should5 grams be delivered per day. Accordingly a formulation of 0.25% maygive a health benefit. It would be noted however that such a low levelis not preferred firstly because the tube fed delivery might only be oneliter or even less, and secondly it will usually be desirable that thelevel of SCFA is somewhat higher. In particular where the individualreceiving the feed has undergone short term trauma and it is desirablethat the SCFA level be increased rapidly. Generally the lower levelsmight be desirable where the individual is tube fed for extendedperiods, and perhaps levels of about 0.5% to about 1.0% might bepreferred, whereas for acute treatment higher levels such as from about2% to about 4% might be desired. Where the degree of substitution of theacetylated starch is higher than the 0.25 of the preparation preparedthere will be a capacity to introduce a higher level of the acylatedstarch. In the case of delivery of other fatty acids such as omega 3fatty acids quite low levels may also give benefits.

It will be understood that enteral feed are also given to suffers ofdiarrhoeal conditions such as cholera, where up to about 4 liters offormulation are given, to compensate for fluid loss associated with thecondition, and accordingly the level of fatty acid delivery agent withinthe formulation might be modified to suit such a rate of application.Similarly enteral formulations are also given to infants where the rateof administration is very low, and may be in the order of 100 ml. The 30grams of fibre estimated by Baghurst et al (supra) is based on anadult's requirement and the requirement for an infant will be smallerthan that, nevertheless a higher concentration may be needed in infantformulations.

Additionally it is anticipated that starch or resistant starchessubstituted with a similar degree of substitution with butyrate andpropionate substitutions will also be able to be administered via anasogastric tube at comparable levels.

It is anticipated that a solution with a viscosity of about 40cP at 25°C. will be able to be used through a feeding tube and accordingly thisthen enables a trial of various formulations of fatty acid deliveryagents.

Example 8 Formulations

The formulations contemplated by this invention vary considerably intheir application. As can be seen from the data above, formulations cangive rise to increased SCFA in a matter of hours and thereforeformulations can be for short term use especially for recovery fromsurgery, or the acute onset of a condition. Additionally the presentinvention might be used for delivery of SCFA where it is required thatthe individual be tube fed for longer periods of time, and accordinglyencompasses the provision of a dry powder to which may be added water tomake up the liquid formulation of the invention. Set out in the tablebelow are a number of formulations the majority of which are devised forhumans both for short and long term application, and to which fatty aciddelivery agent can be added.

TABLE 13 Nasogastric Formulations Nutri- Nutri- son Nutrison son multilow Osmo- En- Product Name UCNF* energy fibre sodium lite sure g per LProtein 67.8 60 40 40 37.2 37.2 Lipid ## 28.2 58 39 39 38.5 37.2Carbohydrate Hydrolysed 161.2 140 94 94 110 110 Starch Sugar 40.3 44 2929 35 35 Fibre 19.89 0 15 0 Gum arabic 7.95 Fructooligo- 7.95 saccharideXylooligo- 3.99 saccharides Vitamins 1.4 0.3 0.3 0.3 0.51 Minerals 9.04.8 4.8 4.8 3.8 Water 780 850 850 841 844 Protein 39.7 44.4 69.9 30 41.762.6 Lipid ## 37.2 36.8 95.6 49.7 10.8 9.1 Carbohydrate HydrolysedStarch 123 116 192.5 80.7 141 81 Sugar 39 36 22.7 29 44 25 Fibre 829 833703 844 867 786 Gum arabic Fructooligo- saccharide Xylooligo-saccharides Vitamins Minerals Water *UCNF (Ulcerative ColitisNasogastric Formula) is an experimental folmulation for pigs. Nutrison ™products are available from Nutricia, Zoetermeer, Holland. Nepro ™,Osmolite ™, Ensure ™, Jevity ™, Vital ™ and Pulmocare ™ are allnasogastric enteral preparations marketed by the Ross Products Divisionof Abbott Laboratories, Columbus, Ohio ## 3% of the lipid is in the formof lecithin.

The fatty acid delivery agent can be added to these formulations assimple additions or they may substitute existing components, especiallywhere the fatty acid delivery agent is a substitute such as for theenergy of the hydrolysed starch or sugar component. It is preferred thatthe fatty acid delivery agent be added during the manufacture of theentire formulation, however it might be desired to add an amount of thefatty acid delivery agent closer to the time of feeding.

The fatty acid delivery agent might be an acetylated resistant starchwhere the acetylation is made according to an aqueous method such as bythe method of example 6. This could be added to any one of theformulations set out in Table 11, simply by addition of dry powder,mixing and dissolving, followed by sterilisation by autoclaving. Theaddition may be at a rate of between 0.5% to about 5% w/v, but it isanticipated that it is likely to be about 2%. Care will be taken not tofreeze the preparation because that may have an adverse effect on thesubstituted starch, and interferes with the process, and a result isthat there is no significant increase in release of SCFA into the largebowel, perhaps as a result of the integrity of the preparation beingcompromised. It is also known that if a DMSO based method of acylationis used then the efficacy of the preparation is also diminished becauseof an increased viscosity so that only much lower levels of thesubstituted starch can be solubilised in the nasogastric preparation.

The acetylated starch is thought likely to be a constituent of both theaqueous phase and the lipid phase of the preparation, and that mayaccount for its observed capacity to stabilise the emulsion.

An alternative example of a nasogastric formulation is a fatty acidsubstituted fructo-oligosaccharide. Such smaller polar molecules arelikely to only be incorporated into the aqueous phase.

The composition of the formulation can be vary as known in the making ofsuch formulations, the addition of the fatty acid delivery agent atlevels that give a detectable increase in the amount of the fatty acidin the large bowel.

The SCFA that are considered to be most beneficial in treatment orprevention of certain colonic disorders are those fatty acids withcarbon chain lengths of 2, 3 and 4, namely acetate, propionate, andbutyrate. However other SCFA may also have beneficial effects andtherefore the term SCFA includes branched chain or substituted shortchain fatty acids. There is doubt as to whether formate (C1) is ofbenefit in adults but may be of benefit in children (Bird et al. CurrIssues Intest Microbiol (2000) 1(1):25–37). SCFA of other lengths mayalso be may also be beneficial so that the term SCFA is to be understoodto include those fatty acids with a chain length in the range of betweenand including 1 to 6 carbons, and accordingly caproic and valerate andisovalerate are included in that description. It is also to beunderstood that fatty acids with longer carbon chain lengths may also bebeneficial and may be covalently bonded to a carrier in a similarfashion. The fatty acids envisioned by this invention are allsusceptible to breakdown before arriving at the colon, unless protected.

Other fatty acids that might also be contemplated by this inventionmight include omega-3 polyunsaturated fatty acids such as linolenic acid(18:2), eicosapentaenoic acid (20:5), docosahexaenoic acid (22:6), andstearadonic acid. The fatty acid delivery agent might includesubstitution by more than one fatty acid, or class of fatty acid.

The carrier to which the SCFA is bonded is preferably a carbohydrate,although other carriers may also be used. Using a carbohydrate hasseveral advantages, largely because of the availability of carbohydratesin commercial quantities and because the effects of carbohydrates in thealimentary tract are relatively well understood. Some forms of carrierare undesirable, for example protein is undesirable because afterfermentation of the protein by products are formed that have an adverseeffect on the colon.

Several forms of carbohydrate may be used as a carrier, these mayinclude soluble non-starch polysaccharides, insoluble non-starchpolysaccharides and oligosaccharides. The carbohydrates used may includebut are not limited to pectins, gums and mucilages, celluloses,hemicelluloses, gums, inulin, oligosaccharides and glucans.

Any suitable source of pectin may be used and the following areillustrative of the types that might be used:—High, medium and lowmethoxylated pectins, high, medium and low gel strength pectins. Thepectin may be derived from any number of sources which sources mayinclude from apples, oranges and lemons.

Any suitable source of gums may be used and the following areillustrative of the types that could be used:—guar, xanthan, arabic,tragacanth, locust bean and psyllium. Modified and artificial gums mayalso act as a carrier.

The soluble non-starch polysaccharides may include long chain inulin,pectin, chitin, β glucans, mucilages, agar, carageenans, alginates andsimilar. Most of these soluble fibres are fermentable for the largestpart.

The insoluble non-starch polysaccharides may include cellulose (forexample derived from oat hull, soybeans, cereal bran) and hemicellulose(mostly branched arabinoxylans or galactans, for example from cereals,potatoes or soybeans). Other celluloses may be used include, but are notlimited to, microcrystalline and other chemically modified celluloses.

Oligosaccharides are understood to comprise any saccharide containing atleast two and up to 10 monosaccharide units, whether of starch (αglucan) or non-starch type. Examples of oligosaccharides that might beused as carriers include fructo- and galacto-oligosaccharides such ashydrolysed inulin and levan (fructans), and short chain amylodextrins,malto dextrins and modifications and derivatives thereof.

The use of simple sugars such as glucose, fructose, galactose, sucroseand lactose, is limited because these may result in osmotic effects thatlead to diarrhoea if administered at levels that are too high, however,it may be possible to use these in dilute solutions to effect animprovement in SCFA delivery.

One of the preferred forms of carrier is a starch because it can befermented by microorganisms in the colon, and accordingly provides forextra nutrients for bacterial bulking in the colon, as well asseparately providing a further source of SCFA additional to the SCFAlinked to the carrier. Furthermore starch is readily availablecommercially.

The starch may be a starch that is digestible in the small intestine.Such digestible starch is protected to some extent from the degradingeffects of α amylases in the small intestine by the SCFA. The extentthat the starch is protected will depend upon the degree ofsubstitution, and if there is only a relatively low degree ofsubstitution, then the starch will rapidly be degraded and there will berelatively good access by the low levels of esterases that exist in theupper alimentary tract to the ester bonds to cleave many of the SCFAsfrom the carrier thereby leading to ineffective delivery to the colon.It may therefore be advantageous to use a resistant starch that isalready resistant to digestion in the small intestine, but that isdigestible in the colon. This will maximize the delivery of starch, andprobably SCFA.

The term starch is understood to include all forms of starch includingmodified starches, and the modification can be physically, enzymically,esterification, oxidation acid cleavage, and reaction with difunctionalreagents, and includes those forms of starch that might be included inthe classification RS1, RS2. RS3 and RS4. Starch can be derived from agreat many sources, and may be derived, for example, be native starchesfrom wheat, potato, tapioca, maize, rice and oats. The carrier may be aresistant starch which resists digestion because of its physical size,granular nature or starch type (e.g. high amylose maize). Such starchincludes those found in potato, green banana and legumes such as peasand may occur additionally due to retrogradation following heattreatment causing granular disruption, hydration and subsequentreassociation in an enzymatic resistant form.

A high amylose starch is in one form a preferred carrier, because theacylation need not necessarily protect the carrier from digestion in thesmall intestine and because resistant starch carried through to thelarge bowel is known to be a particularly good substrate for colonicfermentation. Such a high amylose starch can be a quite high amylosestarch having perhaps greater than 60% amylose or more preferably higherthan 80% amylose. Examples of such starches are those available fromGoodman Fielder Melbourne, Australia under the name Hi Maize™.

It is to be understood that the carbohydrates listed may be modified,either singly or multiply though the use of:—

-   -   heat and/or moisture    -   physical treatment (e.g. ball milling)    -   enzymatic treatment (e.g. α or β amylase, pullulanase or the        like)    -   chemical hydrolysis (wet or dry using liquid or gaseous        reagents)    -   esterification (eg chemical with propylene oxide)    -   oxidation    -   cross bonding with difunctional reagents (e.g. sodium        trimetaphosphate, phosphorous oxychloride)    -   carboxymethylation        or other forms of modification known to those practiced in the        art. These can occur in aqueous and nonaqueous environments.        This list of modifications is not intended to be exhaustive or        limiting.

Where it is desired to deliver only one SCFA then a non-digestiblecarrier, i.e. one that is not degraded by bacterial enzymes of the colonis preferably used, leading to more accurate control over delivery of asingle SCFA, and this may have beneficial effects on the treatment orprevention of certain disorders. The degree of substitution coupled withthe quantity of the agent ingested can be used to regulate the level ofone or more SCFA delivered to the colon.

The invention is beneficial in the maintenance of visceral health inadults children and infants, and includes the method of reducing therisk of any one or more one of the gastrointestinal disorders selectedfrom the following; cancer, constipation, diverticulitis, colitis andirritable bowel and infectious conditions such as diarrhoea and includesthe steps of orally taking an effective dose of the agent according tothis invention at regular intervals. Additionally the invention mightinclude a method for recovery from a medical treatment, the treatmentresulting in an injury to the large bowel, such as surgery or treatmentof a bowel cancer such as by chemotherapy.

The daily dosage rate for a SCFA substituted onto a resistant starchsuch as a resistant maize starch at a degree of substitution of 0.25 maybe in the range of about 5 to 80 grams per day although other dosagerates may be employed, and perhaps most preferably about 40 grams perday. It would be expected that similar dosages rates would beappropriate for other forms of the agent.

It is to be understood that this invention also has application to bothanimals as well as humans and accordingly the SCFA substituted carriercan be used either in the treatment of animal colonic disorders or inthe prevention of colonic disorders and may therefore be included invarious forms of pet formulation or food for animals of commercialimportance such as pigs and horses.

The bond between the fatty acid and the carrier is one that can becleaved by an agent in the bowel to give free fatty acid which can thenbe absorbed. It is to be understood that the cleavage can be either by asingle enzyme, or may take a second step where that enzyme is present inor around the colon.

The bond between the fatty acid and the carrier is preferably an esterbond, because the capacity of the microbial flora of the large bowel tohydrolyse ester bonds is far greater than is the capacity of otherportions of the alimentary tract to do so. Furthermore because hydroxylgroups are generally abundant amongst many carbohydrates there is apotential for a large range of densities of substitution and the abilityto substitute is relatively easy.

Other forms of bonding may include amide bond to amino sugars, howeversuch sugars are relatively rare in unmodified carbohydrates, and therarity limits the extent of substitutions that might be made, oralternatively limits the usefulness to modified carbohydrates, some ofwhich might have other specific advantages. Alternatively the link maybe different where substituted fatty acids are used.

It might also be desired to add further components for example specificvitamins, minerals water and fat soluble anti-oxidants and additionalpharmaceutical therapeutics or additives.

The degree of substitution can depend on the desired outcome, and degreeof bulk or bacterial build-up that is desired. For example where a SCFAis bonded to a carbohydrate it is considered unlikely that the esteraseswill be able to access the ester bond between the sugar moiety and theSCFA moiety if more than one SCFA is present per carrier residuemolecule. Furthermore it is likely that the surface characteristics ofthe carbohydrate will be modified to an extent that the carbohydratewill no longer be water soluble. In one form it is preferred that thedegree of substitution be less than one per sugar moiety. However inanother form it might be desired that the fatty acid delivery agent issoluble in the lipid phase of the nasogastric feed, and higher degreesof substitution might be acceptable than where the fatty acid deliveryagent was to have been water soluble.

The term degree of substitution, as will be understood, not to implythat each carrier molecule is evenly or equally substituted, but is tobe taken as meaning an average degree of substitution. As in mostsubstitution reactions, product molecules with a range of substitutionswill result.

Where a digestible starch is used it is considered unlikely that anysignificant protection to cleavage will result if less than one SCFA isbonded for every twenty sugar molecules, accordingly in a preferred formof the first aspect of the invention the degree of substitution isselected from within the range of 0.05 to 1 SCFA per sugar moiety.Generally however for ease of synthesis and handling a range of betweenabout 0.1 and 0.5 is convenient. Other carbohydrates however are ablestill to be handled and solubilized where the degree of substitution isgreater than one and therefore generally the degree of substitution isselected from the range of 0.05 to 2, and perhaps most conveniently is0.25.

One of the major limitations of providing a source of SCFA for deliveryenterally is that free fatty acids are readily degraded before reachingthe colon. Other sources of SCFA such as resistant starches can bedelivered only in diminished quantities or in quantities that are notfully controllable such as where the resistant starches sediment becausethe granular nature of the resistant starch particles. Additionally, andespecially in the case of naive recipient such as are often the case inpatients requiring nasogastric enteral feed, the presence of a bacterialpopulation capable of giving a high level of SCFA is not necessarilyalways present, whereas enzymes capable of cleaving the typical ether orester bonds are far more pervasively present.

Thus where a hopitalised patient who for example requires surgery toaddress colon cancer, and who has had antibiotic treatment, themicroflora will be considerably compromised. The delivery of anasogastric formulation of at least some embodiments of this inventioncan provide for an increased amount of SCFA within the colon in theshort space of time of a few hours giving the known benefits forrecovery that such SCFAs have.

1. An enteral formulation for nasogastric delivery comprising: a) anamino acid source, b) a carbohydrate source, c) a lipid source, and d) afatty acid delivery agent, being a fatty acid covalently bonded to acarrier molecule by a bond hydrolysable in the colon to thereby releasethe fatty acid, the covalent bonding providing a protective effect toboth the carrier and fatty acid from degradation in the stomach or smallintestine, said carrier being any one of a starch, a non-starchpolysaccharide, or oligosaccharide the fatty acid delivery agent beingpresent in the formulation range of 0.25% w/v through to 5% w/v, andwherein the formulation can be delivered through an enteral feedingtube.
 2. An enteral formulation for nasogastric delivery as in claim 1wherein the formulation is capable of being stored for at least 24 hoursand not forming a gel viscous solution or precipitate that is not easilyresuspended.
 3. An enteral formulation for nasogastric delivery as inclaim 1 wherein the enteral formulation is also an elemental formulationand includes a mineral source and a vitamin source.
 4. An enteralformulation for nasogastric delivery as in claim 1 wherein the fattyacid is a short chain fatty acid (SCFA).
 5. An enteral formulation fornasogastric delivery as in claim 4 wherein the SCFA comprises a carbonchain length between 1 and
 10. 6. An enteral formulation for nasogastricdelivery as in claim 4 wherein the SCFA comprises a chain length between2 and
 4. 7. An enteral formulation for nasogastric delivery as in claim1 wherein the fatty acid is a SCFA or an omega 3 fatty acid, an omega 6fatty acid or stearadonic acid.
 8. An enteral formulation fornasogastric delivery as in claim 7 wherein the omega 3 fatty acid isselected from the group consisting of linolenic acid, eicosapentaenoicacid, and docosahexaenoic acid, and the omega 6 fatty acid is linoleicacid.
 9. An enteral formulation for nasogastric delivery as in claim 1wherein the carrier is a non-starch polysaccharide or oligosaccharide.10. An enteral formulation for nasogastric delivery as in claim 9wherein the non-starch polysaccharide is selected from the groupconsisting of inulin, chitin, β glucans, mucilages, agar, carageenansand gums including guar, arabic, xanthan, tragacanth, locust bean andpsyllium.
 11. An enteral formulation for nasogastric delivery as inclaim 4 wherein the carbohydrate is a starch.
 12. An enteral formulationfor nasogastric delivery as in claim 11 wherein the starch is a starchdigestible in the small intestine.
 13. An enteral formulation fornasogastric delivery as in claim 11 wherein the starch is a starchresistant to digestion in the small intestine.
 14. An enteralformulation for nasogastric delivery as in claim 13 wherein the starchis a high amylose starch.
 15. An enteral formulation for nasogastricdelivery as in claim 11 wherein the starch is a modified starch.
 16. Anenteral formulation for nasogastric delivery as in claim 15 wherein thestarch is modified through the use of any one or more of the following,heat and/or moisture, physically, enzymatically, chemical hydrolysis,esterification, oxidation, cross bonding with difunctional reagents, andcarboxymethylation.
 17. An enteral formulation for nasogastric deliveryas in claim 1 wherein the bond is selected from the group consisting ofa ester bond, an ether bond or an amide bond.
 18. An enteral formulationfor nasogastric delivery as in claim 11 wherein the the carbohydrate hasa degree of substitution ranges from 0.05 acyl group per saccharide unitto 2 acyl groups per saccharide unit.
 19. An enteral formulation fornasogastric delivery as in claim 11 wherein the the carbohydrate has adegree of substitution ranges from 0.1 acyl groups per saccharide unitto 0.5 acyl group per saccharide unit.
 20. An enteral formulation fornasogastric delivery as in claim 4 wherein the carrier is a starch andthe formulation having by weight 0.25% to about 5% of the fatty aciddelivery agent.
 21. An enteral formulation for nasogastric delivery asin claim 4 wherein the carrier is a starch and the formulation having byweight 0.5% to about 4% of the fatty acid delivery agent.
 22. An enteralformulation for nasogastric delivery as in claim 4 wherein the carrieris a starch and the formulation having by weight about 2% of the fattyacid delivery agent.
 23. A method of elevating the level of a fatty acidin the colon of a human or animal, including the step of delivering afatty acid delivery agent in a physiologically acceptable medium througha feeding tube to elevate the level of the fatty acid, the fatty aciddelivery agent being a fatty acid covalently bonded to a carriermolecule by a bond hydrolysable in the colon to thereby release thefatty acid, the covalent bonding providing a protective effect to boththe carrier and fatty acid from degradation in the stomach or smallintestine, said carrier being a starch, a non-starch polysaccharide oran oligosaccharide, the fatty acid delivery agent being present in theformulation range of 0.25% w/v through the 5% w/v.
 24. The method ofclaim 23 wherein the physiological acceptable medium is an enteral feedformulation, including, a) an amino acid sequence, b) a carbohydratesource, and c) a lipid source.
 25. The method of claim 23 wherein thefatty acid is a SCFA.
 26. The method of claim 25 wherein the carrier isa starch.
 27. The method of claim 23 wherein the level of the fatty acidwithin the large bowel is elevated within a time period of 6 hrs. 28.The method of claim 25 wherein the level of the SCFA within the largebowel is elevated within a time period of 4 hrs.
 29. The method of claim25 wherein the level of the SCFA within the large bowel is elevatedwithin a time period of 2 hrs.
 30. The method of claim 26 wherein theenteral formulation is delivered through a nasogastric tube.
 31. Themethod of claim 26 wherein the starch is a resistant starch.
 32. Themethod of claim 31 wherein the resistant starch is a high amylosestarch.
 33. The method of claim 32 wherein the SCFA is selected from thegroup consisting of acetate, propionate and butyrate.
 34. The method ofclaim 33 wherein the quantity of fatty acid delivery agent delivered isbetween 5 and 80 gm/day.
 35. The method of claim 33 wherein the quantityof fatty acid delivery agent delivered is between about 10 and 60gm/day.
 36. The method of claim 33 wherein the quantity of fatty aciddelivery agent delivered is between about 40 gm/day.
 37. The method ofclaim 34 wherein no more than 2 litres of the enteral formulation isdelivered within a 24 hour time period.
 38. The method of claim 34wherein no more than 1 liter of the enteral formulation is deliveredwithin a 24 hour time period.
 39. The method of claim 34 wherein thefatty acid delivery agent is present in the formulation at about 2% byweight of the formulation.
 40. An enteral formulation for nasogastricdelivery as in claim 1 wherein the carrier molecule is selected from thegroup consisting of a non-starch polysaccharide and/or oligosaccharide:the non-starch polysaccharide being selected from the group consistingof inulin, chitin, β-glucans, mucilages, agar, carageenans, gums,cellulose, and hemicellulose, or the gum being selected from the groupconsisting of guar, arabic, xanthan, tragacanth, locust bean andpsyllium, or the cellulose being selected from the group of cellulosesderived from oat hullo, soybeans and cereal bran, microcrystallinecelluloses, methyl celluloses, hydroxypropylmethyl cellulose andcarboxymethylcellulose, or the oligosaccharide being selected from thegroup consisting of fructooligosacchardies, galactooligosaccharides,short chain amylodextrins and maltodextrins and modifications andderivatives thereof.
 41. The formulation of claim 1 wherein theviscosity of the formulation at 25° C. is no greater than 40cP.
 42. Theformulation of claim 1 wherein The polysaccharide is fermentable in thecolon.
 43. The method of claim 23 wherein the physiological acceptablemedium is water.
 44. The method of claim 23 wherein the level of fattyacid within the large bowel is elevated within a time period of about 1hour.
 45. The method of claim 23 wherein the human or animal suffersfrom a gastrointestinal condition and said elevation in level is rapidin relation to an increase in fatty acid levels due to fermentation ofingested carbohydrate so that at least one of the effects of saidcondition are ameliorated rapidly after administration.
 46. The methodof claim 45 wherein the condition is an acute condition in whichincreased levels of fatty acid are beneficial and levels of the fattyacid need to be increased within tree hours of delivery of the fattyacid delivery agent to a pan of the bowel.
 47. The method of claim 45wherein the concentration of fatty acid delivery agent is greater than1% w/v.
 48. The method of claim 23 wherein the fatty acid is a shortchain fatty acid (SCFA).
 49. The method of claim 48 wherein the SCFAcomprises a carbon chain length between 1 and
 10. 50. The method ofclaim 48 wherein the SCFA comprises a carbon chain length between 2 and4.
 51. The method of claim 47 wherein the condition is selected from thegroup consisting of diarrhea, post operable surgery, gastrointestinalbacterial infections, antibiotic treatment chemotherapy and radiotherapytreatments.
 52. The method of claim 26 wherein the starch is a modifiedstarch.
 53. The method of claim 52, wherein the starch is modifiedthrough the use of any one or more of the following, heat and/ormoisture physically, enzymatically, chemical hydrolysis, esterification,oxidation, cross bonding with difunctional reagents, andcarboxymethylation.